Variant rs776797592 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_015909.4(NBAS):c.2950del(p.Ile984LeufsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,613,392 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

NBAS
NM_015909.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.51

Variant links:

Genes affected

NBAS (HGNC:15625): (NBAS subunit of NRZ tethering complex) This gene encodes a protein with two leucine zipper domains, a ribosomal protein S14 signature domain and a Sec39 like domain. The protein is thought to be involved in Golgi-to-ER transport. Mutations in this gene are associated with short stature, optic nerve atrophy, and Pelger-Huet anomaly. [provided by RefSeq, Oct 2012]

NBAS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-15402288-AT-A is Pathogenic according to our data. Variant chr2-15402288-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 501319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-15402288-AT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBAS	NM_015909.4 linkuse as main transcript	c.2950del	p.Ile984LeufsTer8	frameshift_variant	26/52	ENST00000281513.10	NP_056993.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBAS	ENST00000281513.10 linkuse as main transcript	c.2950del	p.Ile984LeufsTer8	frameshift_variant	26/52	1	NM_015909.4	ENSP00000281513	P1	A2RRP1-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000108

AC:

AN:

251026

Hom.:

AF XY:

0.0000885

AC XY:

AN XY:

135668

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000267

AC:

390

AN:

1461284

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

197

AN XY:

726946

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000327

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000158

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000151

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30609409, 31589614, 31980526, 31964843, 34386911, 31015584, 31761904) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 26, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	NBAS: PVS1, PM2:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Ile984Leufs*8) in the NBAS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NBAS are known to be pathogenic (PMID: 26073778, 26541327, 27789416, 28031453). This variant is present in population databases (rs776797592, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with NBAS-related disorders (PMID: 31761904). ClinVar contains an entry for this variant (Variation ID: 501319). For these reasons, this variant has been classified as Pathogenic. -

Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 02, 2023

Variant summary: NBAS c.2950delA (p.Ile984LeufsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic in ClinVar. The variant allele was found at a frequency of 0.00011 in 251026 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in NBAS causing Liver Failure Acute Infantile, Type 2 (0.00011 vs 0.0011), allowing no conclusion about variant significance. c.2950delA has been reported in the literature in individuals affected with NBAS-related disorders (example: Staufner_2020). The following publication has been ascertained in the context of this evaluation (PMID: 31761904). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Short stature-optic atrophy-Pelger-HuC+t anomaly syndrome;C3809651:Infantile liver failure syndrome 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 28, 2022

- -

Infantile liver failure

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 01, 2017

The p.Ile984LeufsX8 variant in NBAS has not been reported in individuals with di sease and has been identified in 9/120,878 of chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs140841721). Althou gh this variant has been seen in the general population, its frequency is low en ough to be consistent with a recessive carrier frequency. This variant is predic ted to cause a frameshift, which alters the protein?s amino acid sequence beginn ing at position 984 and leads to a premature termination codon 8 amino acids dow nstream. This alteration is then predicted to lead to a truncated or absent prot ein. Homozygous or compound heterozygous mutations in NBAS have been associated with Infantile liver failure syndrome 2. In summary, this variant meets our cr iteria to be classified as pathogenic for Infantile liver failure syndrome 2 in an autosomal recessive manner based on low frequency in controls and functional prediction -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over